WO1982000142A1 - Prostaglandins - Google Patents

Prostaglandins Download PDF

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Publication number
WO1982000142A1
WO1982000142A1 PCT/GB1981/000116 GB8100116W WO8200142A1 WO 1982000142 A1 WO1982000142 A1 WO 1982000142A1 GB 8100116 W GB8100116 W GB 8100116W WO 8200142 A1 WO8200142 A1 WO 8200142A1
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group
bicyclo
compound according
substituted
aliphatic hydrocarbon
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PCT/GB1981/000116
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English (en)
French (fr)
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Res Dev Corp Nat
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Jones R
Wilson N
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Publication of WO1982000142A1 publication Critical patent/WO1982000142A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0058—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a not condensed ring different from a five-membered ring
    • C07C405/0066—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a not condensed ring different from a five-membered ring to a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0091—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is bridged condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • C07C45/305—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation with halogenochromate reagents, e.g. pyridinium chlorochromate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/44—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reduction and hydrolysis of nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/225—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/47—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/26—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • This invention relates to biologically active compounds and in particular to certain novel compounds exhibiting activity at thromboxane receptor sites.
  • Thromboxane A 2 (TXA2) , which is derived from arachidonic acid via prostaglandin H 2 (PGH 2 ) , is implicated in several potentially noxious actions on various body systems, including platelet aggregation, bronchoconstriction and pulmonary and systemic vasoconstriction.
  • TXA 2 may be involved in the normal sealing of blood vessels following injury but in addition may contribute to pathological intravascular clotting or thrombosis.
  • the constrictor actions of TXA 2 on bronchiolar, pulmonary vascular and systemic vascular smooth muscle may be important in the development of several anaphylactic conditions including bronchial asthma. There is also some evidence to implicate PGH 2 and TXA 2 in the genesis of inflammation.
  • the present invention comprises a compound of formula (I)
  • R 1 is a
  • R 2 is hydrogen, an aliphatic hydrocarbon group or an aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group, and R is a group
  • R 3 is an aliphatic hydrocarbon group, an aromatic group or an aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group
  • R 4 is an aliphatic hydrocarbon group which is substituted through an oxygen atom by an aliphatic hydrocarbon group which is itself substituted by an aromatic group
  • R 5 is an aliphatic hydrocarbon group, an aromatic group or an aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group
  • R 6 is hydrogen, an aliphatic hydrocarbon group, an aromatic group or an aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group, with the proviso that when
  • R is a group -OR 3 , -NH.COR 3 or -NH.CO.NHR 3 then
  • the invention also extends in general to other pharmaceutically acceptable bioprecursors for the compounds described above, such a bioprecursor being a compound having a structural formula different from the active compound but which upon administration is converted thereto in vivo.
  • Modifications of the 6-carboxyhex-2-enyl group which may be made in compounds according to the present invention are of two types. Firstly, there are modifications which involve alteration of the 6-carboxyhex-2-enyl group by one, or where appropriate by a combination, of the following: (a) reduction of the double bond optionally accompanied by the replacement of a carbon atom at the 2,3 or even 1 position by a sulphur or particularly an oxygen atom; (b) alteration of the positon of the double bond, for example to the 3, 4 position; and (c) shortening or lengthening of the carbon chain, particularly by one or two methylene groups and conveniently at the end of the chain adjacent to the carboxy group.
  • the second form of modification involves conversion of the carboxy group to a functional derivative including salts thereof.
  • Functional derivatives described in the prostaglandin art are of particular interest, including esters such as alkyl esters, amides such as those containing the group -CONHSO 2 CH 3 and variants thereon, and salts with various physiologically acceptable cations.
  • Specific examples of salts are those with an alkali metal such as sodium or with quaternary ammonium ions or amines such as tris (the symbol tris represents the compound 2-amino-2-hydroxymethylpropane 1,3-diol).
  • a 2-phenylethyl group is preferred to a 1-phenylethyl or phenylmethyl (benzyl) group.
  • Good levels of activity have been achieved with compounds in which R 2 is one of hydrogen, ethyl and especially methyl.
  • R are of particular interest.
  • the group R 3 can be of various forms.
  • Aliphatic hydrocarbon groups constituting R 3 may conveniently be of one to five, six, seven, eight, nine, ten or even more carbon atoms, being, for example an alkyl group and including branched or unbranched acyclic alkyl groups such as methyl, ethyl, propyl, butyl, amyl, etc., cyclic alkyl groups such as cyclopentyl, cyclohexyl etc., and also combinations thereof such as cyclohexylmethyl etc.
  • Aromatic groups constituting R 3 are of greater interest than the unsubstituted aliphatic hydrocarbon groups and may be hydrocarbon or heterocyclic groups which may be unsubstituted or substituted.
  • the term 'aromatic group' as used herein extends to groups derived from ring systems having aromatic properties but in which the ⁇ -electron system is not fully delocalised over the entire ring system, such groups including those derived from fluorene, dihydrobenzoxazole, dihydrobenzothiazole N-methyldihydrobenzothiazole, and 1,2,4,5-dibenzocycloheptane.
  • heterocyclic groups which conveniently contain one, two or more, similar or different nitrogen, oxygen or sulphur atoms, are more generally linked through a carbon atom so that, in the case of a pyridyl group, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl are of particular interest.
  • Both the aromatic hydrocarbon and the heterocyclic groups may be substituted, by one or more of various types of substituent, particularly by alkoxy groups, for example those containing alkyl groups of 1,2,3 or more carbon atoms as described above and especially methoxy, and by substituents being or containing a halogen residue, for example chloro and especially fluoro, and also halogen substituted alkyl groups such as CF 3 .
  • substituents are sulphamoyl groups which may optionally be N-substituted, amino groups which may be free or substituted, for example dimethylamino, hydroxyl, nitro, and alkyl groups, for example of 1 to 3 carbon atoms or otherwise as described above, etc.
  • Substitution may be present at one or more of the ortho, meta and para positions of a phenyl ring or at a combination of two or more such positions (including two similar positions) , for example at the 2 and 4 positions.
  • Substitution and the position of substitution for example by alkoxy groups and groups being or containing a halogen, may have a definite effect upon the level of activity of a compound.
  • groups R 3 which are aliphatic hydrocarbon groups substituted directly or through a sulphur or particularly an oxygen atom by an aromatic group.
  • the aliphatic groups may be of a similar size to those described above but preferably comprise an acyclic group, conveniently of three carbon atoms, particularly of two carbon atoms and especially of one carbon atom, although this acyclic group may carry a cyclo-alkyl group as well as an aromatic group.
  • Similar aromatic hydrocarbon and heterocyclic residues are generally of interest for attachment to the aliphatic groups as have already been described above, the aromatic hydrocarbon groups again generally being of rather more interest than the heterocyclic groups.
  • Heterocyclic groups where used, are of most interest in this context when linked to the aliphatic hydrocarbon group through a hetero atom such as in pyrid-1-yl. Substitution of an aliphatic hydrocarbon group, partiuclarly terminally, by two or even three aromatic groups, for example phenyl, is of particular interest, whilst also of interest are acyclic groups carrying terminally both an aromatic group, for example phenyl, and a cyclo-alkyl group, for example cyclohexyl.
  • R 3 is or contains a substituted aronatic group
  • some positions of substitution may be of more interest than others in particular cases.
  • R 3 is a substituted benzyl group the order of interest is often o-p>m
  • R 3 is a substituted phenyloxyethyl group it is o>m>p
  • R 3 is a substituted phenyl group it is m ⁇ p>o.
  • it may be of value to have a substituent at each position as when the group R 3 is 3,4-dimethoxyphenyl.
  • R which terminate in a grcup R
  • R is a group -OR 3 or a group -A-R 3 in which A is -NH.CO-, -NH.SO 2 -, -NH.CO.NH-or -NH.CS.NH-.
  • Very good levels of activity have been obtained with compounds in which R is a group -OR 3 or particularly a group
  • one group R 3 containing an aliphatic hydrocarbon group substituted by an aromatic group which is of some interest in groups -A-R 3 is that consisting of an ethyl group substituted at the 1-position by a napthyl group, for example a napth-1-yl group.
  • the reagent H 2 N.NH. CO.NHCH(CH 3 )-napth-1-yl which may be used to prepare compounds (I) containing such a group, is of particular interest since it contains an asymmetric carbon atom and may be obtained in optically active form. Examples of specific groups R 3 are:
  • the group R 4 is an aliphatic hydrocarbon group which is substituted through an oxygen atom by an aliphatic hydrocarbon group which is itself substituted by an aromatic group and preferences as regards both aliphatic hydrocarbon groups and the aromatic group are broadly as expressed above in the case of the group R 3 .
  • the aliphatic hydrocarbon group attached to the oxime oxygen atom is preferably of more than one carbon atom, for example being of three or particularly two carbon atoms, whilst the aliphatic hydrocarbon group substituted by an aromatic group is preferably of one to three carbon atoms, for example one carbon atom.
  • This latter aliphatic hydrocarbon group may conveniently be terminally substituted by one, two or even three aromatic groups although two or only one aromatic groups are preferred and these may conveniently be phenyl groups or substituted phenyl groups as described above in relation to R 3 .
  • groups R 5 which are aromatic groups it will be appreciated that there will not be such a close correspondence to the groups R 3 described above as these aromatic groups, because of their divalent nature, generally cannot derive from many of the aromatic systems described above in which the ⁇ -electrons are fully deloca lised over the whole ring system, such as those comprising a single benzene or pyridine ring.
  • aromatic groups constituting R 4 are therefore usually of the type described hereinbefore in which the ⁇ -electron system is not fully delocalised over the entire ring system and, indeed, this type of residue is one of those preferred in the case of R 5 , specific preferences among such types of aromatic group being as discussed above in relation to R 3
  • Another preferred type of group R 5 is a methylene group in which both hydrogen atoms are substituted by an aromatic group, for example such as phenyl, so that the double bonds of the system are in conjugation with the aromatic system.
  • R 6 the preferences among aliphatic, aromatic and araliphatic groups R 6 generally correspond to those indicated above for R 3 alth ugh aliphatic hydrocarbon groups are of rather more interest than is generally the case and, with the araliphatic groups, direct substitution by an aromatic group is preferred to substitution through an oxygen or sulphur atom.
  • R 6 an important additional alternative is for R 6 to be hydrogen.
  • the group -NH.CO.CH 2 either contains a group R 6 which is identical to the group R 3 , for example both being an unsubstituted aliphatic hydrocarbon group or one substituted directly by an aromatic group, or a group R 6 which is hydrogen.
  • specific examples of the larger group are -NH.CO.CH 2 .N(CH 2 C 6 H 5 ) 2 and -NH.CO.CH 2 N(C 2 H 5 ) 2 or
  • compounds according to the present invention may contain, in the order shown previously, one of the following types of ring system: bicyclo [2,2,1] heptane, bicyclo [2,2,1] hept-2Z-ene, 7-oxa-bicyclo [2,2,1] heptane, 7-oxa-bicyclo [2,2,1] hept-2Z-ene, bicyclo [2,2,2] octane, bicyclo [2,2,2] oct-2Z-ene, 6,6-dimethyl-bicyclo [3,1,1] heptane, cyclohexane, cyclohexane and hydroxycyclopentane.
  • the 6,6-dimethyl-bicyclo [3,1,1] heptane ring system may be substituted in either of two ways, corresponding to reversal of the substituents shown at the a and b positions. It will be appreciated that the bridged ring systems present in compounds according to the present invention show a range of degrees of asymmetry.
  • the 6,6-dimethyl-bicyclo [3,1,1] heptane ring system is sufficiently asymmetric for reversal of the substituents at the a and b positions, as shown on page 2, to result in a different structural isomer, and thus a different compound (I) , both types of compound (I) containing the 6,6-dimethyl-bicyclo [3,1,1] heptane ring system being covered by the present invention.
  • bridged ring systems which may be saturated or unsaturated
  • the former are usually preferred, particularly in the case of the compounds containing an oxygen bridging group, as unsaturation generally confers lower stability whilst the level of biological activity is generally substantially similar.
  • Isomers of particular interest are shown below in one of the two enantiomorphic forms which can exist in each case, the other enantiomorph having a structure which is the mirror image of that shown.
  • the unsaturated ring system is illustrated where the ring system may be saturated or unsaturated and the symbol B represents -CH 2 - (position 7), -O- (position 7) or -CH 2 CH 2 -(positions 7 and 8).
  • the bicyclo [2,2,2] octane system possesses a greater degree of symmetry than the other bridged ring systems, as the two bridging groups attached together at the bridge positions (1 and 4) are identical, both being -CH 2 CH 2 -.
  • the trans isomer is preferred and can exist in two enantiomorphic forms, the endo, exo type isomerism which can occur with the other bridged ring systems cannot arise.
  • substituent R 1 is a 6-carboxyhex-2-enyl group or a group modified therefrom but still containing the double bond
  • the configuration about this bond is preferably cis (Z) rather than trans (E).
  • the compounds of the present invention will in most cases additionally be resolvable into enantiomorphic forms and one among these may be preferred by virtue of biological activity or physical properties.
  • Single enantiomers may be obtained either by the use of an optically active starting material or by resolution of a pair of enantiomorphs.
  • Specific compounds according to the present invention include the various compounds described in the Examples as well as the analogues thereof in which a 6-carboxyhex-2Z-enyl group is replaced by a 6-carboxyhexyl group and/or the group R 2 is the other two of the groups hydrogen, methyl and ethyl than the one appearing in the specific compound in question, for example the compound
  • Compounds of formula (I) according to the present invention may be prepared by reacting a compound of formula (II) with a reagent ZNH 2 , Y being either R 1 as defined above for compound (I) or a precursor for R 1 and Z being either R as defined above for compound (I) or a precursor for R, and the other symbols being as defined for compound (I), and where appropriate converting the group Y and/or the group Z in the resultant product into the groups R 1 and R, respectively, of the compound (I).
  • Z and conveniently also Y correspond to the corresponding groups R and R 1 in the compound (I) .
  • a convenient form of intermediate for the preparation of all the various compounds (I) according to the present invention is a compound of formula (III) in which the symbols have the meaning indicated for formula (II).
  • the compound of formula (III) may conveniently be reacted with a Grignard reagent of the form R 2 MgHalogen, followed by oxidation of the secondary alcohol of formula (IV) so formed, for example using Jones reagent, and the resulting compound of formula (II) containing the desired group R 2 reacted with the reagent ZNH 2 as indicated previously
  • the unsaturated bicyclic ring systems bicyclo [2,2,1] hept-2Z-ene, 7-oxa-bicyclo [2,2,1] hept-2Z-ene and bicyclo [2,2,2] oct-2Z-ene may be prepared by omitting or modifying the reduction step which converts the unsaturated ring system which is produced initally in each case to the corresponding saturated ring system, for example by omitting the catalytic reduction employing H 2 /Pd in the route shown on page 72.
  • the synthesis of the bicyclo [2,2,1] hept-2Z-ene compound of formula (III) is described in detail in U.K.
  • stereoisomers are obtainable by modified routes.
  • ⁇ -pinene may be obtained in both optically active forms thus providing a route to (+)-nopol and (+) -myrtenol as alternative starting materials for use in the routes described in Examples 7,8 and 9.
  • One procedure for doing this involves protection of the alcohol group, for example as an ester, removal of the acetal and reaction of the aldehyde group with a methoxymethyl phosphonium ylide. Following this the group R 1 can be built up further and the hydroxymethyl group reduced to a formyl group.
  • the group Y in the compound of formula (II) may similarly contain a free carboxy group or may, as illustrated in the scheme on page 72, contain a carboxy group in protected form, for example as an ester and particularly as the methyl ester which may conveniently be formed with diazomethane.
  • a protecting group may then be removed, for example by de-esterification using KOH/CH 3 OH/H 2 O. Such protection will generally lead to a slightly greater overall yield of the compound (I) from the compound (II) .
  • the reactants ZNH 2 are most usually of the form RNH 2 and may be prepared by various procedures known in the art and illustrated in the Examples, the procedures illustrated generally being applicable to a variety of forms of groups R 3 , R 4 and R 5 in R.
  • the reagents H 2 N.NH. CO.R 3 may conveniently be prepared by the reaction of hydrazine with the corresponding ester for example the ethyl ester, R 3 .CO 2 C 2 H 5 .
  • the reagents H 2 N.NH.CO.NHR 3 may be prepared by the reaction of hydrazine with the corresponding N-substituted carbamate, for example the ethyl carbamate, R 3 NHCO 2 C 2 H 5
  • Reagents H 2 N.NHCSNHR 3 may be prepared very conveniently through the reaction of the corresponding primary amine R 3 NH 2 with carbon disulphide in the presence of dicyclohexylcarbodiimide, followed by reaction of the resulting isothiocyanate, R 3 NCS. with hydrazine.
  • Reaction between the compound of formula (II) and the reactant ZNH 2 is often effected either with its HCl salt in pyridine or with the free base in a neutral solvent, for example tetrahydrofuran or dioxane, some degree of heating often being used as shown in the Examples.
  • R 3 is a methyl group substituted by two aromatic groups, for example where R 3 is a diphenylmethyl or a fluoren-9-yl group and groups not of this type are accordingly preferred in the case of groups R of type -NHR 3 .
  • Modification of the 6-carboxyhex-2-enyl group may be effected through the initial introduction of a modified group or by modification of this group during or at the end of the synthesis, ester formation conveniently being effected, for example, at the stage indicated hereinbefore and amides similarly being prepared by conventional procedures. Indeed, the procedures for effecting the various modifications indicated above will be apparent from the considerable literature existing on prostaglandin chemistry.
  • a saturated ring system where, as is the case in the scheme shown on page 72, a precursor of structure
  • 6-carboxyhexyl group involves an initial Diels-Alder reaction of
  • 3-oxa-6-carboxyhexyl group is similarly best effected at an early stage of the synthesis.
  • a convenient route for doing this involves the use of a compound of structure
  • residue X is a saturated one, such as 6,6-dimethyl-2- (2'-hydroxyethyl)-bicyclo [3,1,1] hept-2-ene, as a starting material.
  • the Konzett-Rossler test showed inhibition of the bronchoconstrictory effect of both 11, 9-(epoxy ⁇ ethano) PGH 2 and the collagen. It is believed that such inhibition is the result of the compounds being thromboxane antagonists and the activity of the compounds is for convenience hereinafter discussed in these terms.
  • Preferred compounds according to the present invention exhibit a pure antagonist activity.
  • Preferred compounds such as the compounds of Examples 1 and 2 are antagonists in the platelet test, block the aggregatory action of arachidonic acid which is converted to TXA 2 by the platelet enzyme system and may or may not block the aggregatory action of ADP which acts via non-TXA 2 - sensitive systems. Moreover, they are pure antagonists in the rabbit aorta strip test but do not block the contractile action of noradrenaline which acts on ⁇ -adrenoceptors. Some activity has also been observed in compounds according to the present invention on guinea pig tracheal muscle.
  • compositions according to the present invention are of interest for the treatment of thrombotic disorders and also for the treatment of anaphylactic disease states, for example as bronchodilators for the treatment of asthma, in hypoxia, etc. They additionally have potential as anti-inflammatory agents. It will be appreciated that the spectrum of activity shown by any particular compound will vary and that certain compounds may be of particular interest in one of these applications whilst other compounds are of particular interest in another of them. Modifications of a compound can have other advantages.
  • esters and other derivatives of the 6-carboxyhex-2-enyl group or modifications thereof can have advantages in relation to slow release depot preparation through conversion in vivo to the active compound containing a free carboxy group, although the low water solubility of the esters must be taken account of.
  • the use of a compound in which the 6-carboxy group is in salt form, for example the sodium salt can be of value due to the enhancement of water solubility which generally results.
  • the compounds may be formulated for use as pharmaceuticals for both animal and particularly human administration by a variety of methods, but usually together with a physiologically acceptable diluent or carrier.
  • the compounds may, for instance, be applied as an aqueous or oily solution or as an emulsion for parenteral administration, the composition therefore preferably being sterile and pyrogen-free.
  • the preparation of aqueous solutions of compounds in which the group R 1 terminates in a free carboxy group may be aided by salt formation.
  • the compounds may also be compounded for oral administration in the presence of conventional solid carrier materials such as starch, lactose, dextrin and magnesium stearate.
  • Alternative formulations are as aerosols, suppositories, cachets, and, for localised treatment, as suitable creams or drops. Without commitment to a rigid definition of dosage, which is difficult in view of the different levels of activity, methods of formulation, and methods of administration, some general guidance may be given.
  • the normal daily dosage which is proposed lies in the range from about 0.1 mg to about 10 mg per kilogram (the average weight of a human being about 70 kg) and particularly from about 1 mg to about 5 mg per kilogram. It will be appreciated, however that dosages outside this range may be considered, for example in the case of topical application to produce a localised thromboxane agonism, and that the daily dosage may be divided into two or more portions.
  • the invention is illustrated by the following Examples.
  • the compounds of the present invention are related to the compounds described and claimed in our U.K. patent applications of numbers 8000278 and 8000279 referred to hereinbefore in which bicyclo [2,2,1] heptanes and hept-2Z-enes are disclosed and claimed which are substituted at the 5-position by a 6-carboxyhex-2-enyl group or a modification thereof, and at the 6-position by a group
  • R 3 represents a group -OR 3 , -NH.CO.R 3 or -NH.CO.NH-R 3 and R 3 includes the groups R 3 described herein.
  • the stereochemistry which the compounds are believed to possess has been indicated.
  • some contamination of a minor nature by other isomers may often be present, i.e. by the other of the pairs of preferred isomers shown on page 16/17 or particularly by the corresponding cis isomer.
  • the compounds are obtained in the form of a racemic mixture but in the case of the compounds of Examples 7,8 and 9 an optically active starting material is used and these compounds are therefore also optically active.
  • the mass spectroscopy data given in these examples is obtained by direct inlet except for those cases where the compound has a substituent R 1 which terminates in an ester grouping when the data is obtained by gas chromatography mass spectroscopy.
  • the free carboxy group of the substituent R 1 is converted to a methyl ester group before the mass spectrum is run (by gas chromatography mass spectroscopy).
  • Such conversion is readily achieved by solution in methanol, using warming and addition of NaHCO 3 as necessary, followed by the addition of an excess of ethereal diazomethane to the methanolic solution, standing, and the removal of solvent.
  • Freshly cracked cyclopentadiene (9.0g) is mixed with 11.0g of the pseudo ester (1). A gentle warming is observed and the mixture is allowed to stand overnight. The n.m.r. spectrum typically shows the formation of the adduct (2) to be complete and the material is taken to the next step without purificatior.
  • the Diels-Alder adduct (2) (10g) is heated in a mixture of triethyl orthoformate (10 ml), dry ethanol (100 ml), and concentrated sulphuric acid (1 ml). The mixture darkens and after 12 hours is cooled and treated with anhydrous potassium carbonate (5g) and ether (150 ml). Water is then slowly added with efficient mixing to neutralise the acid. The product is extracted with ether, washed with water and distilled to give the title compound as an oil (7.3g, 63%), b.p. 115 - 120°C/0.3 mm.
  • the ester (4) (27g) is added in ether to a 10% excess of lithium aluminium hydride (2.1g) in ether with stirring at reflux temperature. The mixture is boiled for 1 hour after the addition and is then quenched by the addition of wet ether followed by 5% aqueous sodium hydroxide to precipitate aluminium salts. The colourless organic phase is dried over magnesium sulphate, filtered and evaporated to give the title compound as an oil (20g, 91%).
  • the tosylate (14g) in 15 ml dimethyl sulphoxide is added to 5g of dry potassium cyanide in 20 ml dimethyl sulphoxide.
  • the mixture is stirred under nitrogen and the temperature slowly raised over 1 hour to 110oC. After 5 hours the reaction mixture is cooled and poured into water.
  • the product is isolated by ether extraction, and purified by distillation to give the title compound (7.8g, 90%), b.p. 115 - 126°C/1.5 mm.
  • the acid acetal (8) (1.8g) is dissolved in 200 ml chloroform and 50 ml of concentrated hydrochloric acid is added to form a two phase system. The mixture is vigorously stirred for 90 minutes and is then extracted with ether and the ethereal solution dried and concentrated.
  • the residual oil is purified by silicic acid chromatography, the oil being applied to the column (prepared by slurrying 10g of Unisil silicic acid - Clarkson Chemical Co., USA - in hexane and pouring into a glass chromatography column) in hexane and elution being carried out with increasing proportions of diethyl ether in hexane up to pure diethyl ether.
  • the chromatography gives the title compound as a colourless oil (1.4g, 83%),
  • the aldehyde/acid (9) (100 mg) is heated at 60°C with benzylthiosemicarbazide (110 mg) in tetrahydrofuran (THF) (5 ml) for 2 hours.
  • THF tetrahydrofuran
  • the THF is removed in vacuo, and the resulting product is purified by silica gel chromatography (10g charge), eluting with a linear gradient from 10% v/v ethyl acetate in benzene to pure ethyl acetate and monitoring the fractions by t.l.c.
  • the chromatography gives the title compound as a yellow oil (85 mg) , ⁇ max
  • the benzylthiosemicarbazide is prepared as follows .
  • Benzylisothiocyanate (4.0g) is slowly added to 1.8g of anhydrous hydrazine in 50 ml dioxane. The reaction mixture is stirred at room temperature, the dioxane is then removed in vacuo and the residue is recrystallised from ethanol to give 4-benzylthiosemi carbazide as a crystalline solid (2.5g), m.p. 127.6°C.
  • Example 2 5-endo (6 '-Carboxyhex-2' Z-enyl) -6-exo- ⁇ 1'- [N-(phenylthio carbamoyl)-hydrazono]-ethyl ⁇ -bicyclo [2,2,1] heptane (1) 5-endo(6 '-Carboxyhex-2 'Z-enyl) -6-exo-( 1 ' -hydroxyethyl) -bicyclo [2,2,1] heptane
  • the dioxane is removed in vacuo, and the resulting product is purified by silica gel chromatography (10g charge), eluting with a linear gradient from 10% v/v ethyl acetate in benzene to pure ethyl acetate and monitoring the fractions by t.l.c.
  • the chromatography gives the title compound as an oil (107 mg) , ⁇ max (CH 3 OH) 277nm, ⁇ max 24, 780, ⁇ (CDCl 3 ) 2.00 (s, 3H) , 5.35 (m,2H), 7.2-7.7 (m, 5H) ,
  • Example 3 5-endo(6'-Carboxyhex-2'Z-enyl)-6-exo- ⁇ 1'-[N-(phenyl thiocarbamoyl) -hydrazono] -propyl ⁇ -bicyclo [2,2,1] heptane (1) 5-endo-(6'-Carboxyhex-2 ' Z-enyl) -6-exo-(1 ' -hydroxypropyl) - bicyclo [2,2,1] heptane
  • the alcohol/acid (1) of the first zone (145 mg) is oxidized with Jones reagent at 0°C in acetone in an exactly analogous manner to that described in Example 2(2) to give the title compound as an oil (95 mg), ⁇ (CDCl 3 ) 9.0 (br, 1H) , 5.35 (m, 2H) , 2.7-0.9 (m, 23H), M + 292 together with 235 (M-57) and 151 (M-141) (as methyl ester - a single peak being obtained on gas chromatography) .
  • the alcohol/acid (1) of the second zone is treated similarly to give the same product (105 mg) .
  • the ketone/acid (2) (100 mg) and phenylthiosemicarbazide (110 mg) in dioxane (5 ml) are heated to 50°C overnight.
  • the dioxane is removed in vacuo, and the resulting product is purified by silica gel chromatography (10g charge) eluting with a linear gradient from 10% v/v ethyl acetate in benzene to pure ethyl acetate and monitoring the fractions by t.l.c.
  • the chromatography gives the title compound as an oil (20 mg, 15%) , ⁇ max (CH 3 OH) 277 nm, ⁇ max 22,380, ⁇ (CDCl 3 ) 9.7 (br, 1H) , 9.1 (br, 1H) , 7.8-7.0 (m,
  • Cyclohexadiene (4.5g) and the maleinaldehyde acid pseudo-ethyl ester described in Example 1(1) (6.4g) are heated together in a thick walled glass tube at 120°C for 10 hours and the product is distilled to give the Diels-Alder adduct of these two compounds in over 90% yield, b.p. 95-97°C/0.2 mm, M + 208.
  • the Diels-Alder adduct (1) (10g) is heated under a Dean and Stark apparatus with 12 ml of ethylene glycol in 100 ml toluene containing a crystal of p-toluenesulphonic acid. After water has ceased to form, half of the solvent is distilled off and the resultant solution of 5-ethoxycarbonyl-6-(1',3'-dioxacyclopent- 2' -yl) -bicyclo [2,2,2] oct-2Z-ene is added to excess lithium aluminium hydride (3g) in 200 ml of dry ether. The addition is performed at a rate which maintains a gentle boiling of the ether (30 to 60 minutes).
  • the nitrile/acetal (4) (7.0g) is stirred in 100 ml of dry toluene under nitrogen at -15oC.
  • Di-isobutylaluminium hydride (42.5 ml of 1M solution in toluene) is added slowly over 25 minutes and the mixture is allowed to warm slowly to room temperature.
  • methanol (10 ml) is slowly added, followed by 200 ml of saturated aqueous sodium hydrogen tartrate.
  • the mixture is stirred at 40oC for 2 hours and the upper organic layer is then separated and the aqueous phase further extracted with ethyl acetate.
  • the combined organic solutions are dried (MgSO 4 ) and evaporated.
  • the yellow oil obtained is chromatographed on Florisil in toluene to give the title compound as an oil (5.8g, 83%), v max
  • the acetal group is removed by stirring this material (3g) with 200 ml of water/dioxane (1:1 v/v) containing 0.1N aqueous hydrochloric acid at 40oC.
  • the mixture is extracted with ether and the ethereal extract is dried (MgSO 4 ) and evaporated to give a residue which is purified by chromatography on silica gel in toluene/ethyl acetate (90:10 v/v) to give the title compound as an oil [2.3g, 48% from (5)], v max (film) 1725 and 1710 cm -1 , ⁇ (CDCl 3 ) 9.73 (s, 1H), 5.5-5.3 (m, 2H) , and 2.2-1.45 (m, 20H) .
  • the phenyl semlcarbazide is prepared as follows. Ethyl-N-phenylcarbamate (8.25g) is refluxed with hydrazine hydrate (3.75g) for 3 hours. The mixture is evaporated to dryness and the residue is treated with ether, and the solid phenyl semicarbazide (1.5g) is filtered off, washed with ether and dessicated, m.p. 122 - 124°C. Note: In a variant of the procedure described in this Example the acid/aldehyde (6) (100 mg) is reacted with p-fluorobenzoic hydrazide (H 2 NNHCO — F) (45 mg) in place of the phenyl semicarbazide
  • Example 2(2) to give 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-acetyl bicyclo [2,2,2] octane as an oil (1.3g), ⁇ (CDCl 3 ) 5.4 (m, 2H), 2.2 (s, 3H) 2.6-1.3 (m, 20H) , M + 292 and also 249 (M-43) and 151
  • the acid/ketone ( 1) (30 mg) is heated at 40oC with phenylthiosemicarbazide [115 mg, prepared as described in Example 2 (3) ] in dioxane for 2 hours.
  • the solvent is removed in vacuo and the residue is purified by gel partition chromatography on a column of Sephadex LH20 substituted with Nedox 1114 olefin oxide to 20% w/w (Lipidex) using as eluant a mixture of (all proportions by volume) 100 parts of hexane, 100 parts of 1,2-dichloroethane, 5 parts of ethanol and 0.1% of the total of glacial acetic acid.
  • the lactone (2) (4.6g), in dry toluene (70 ml) is treated with stirring at 0oC with 24 ml of a 25% w/v solution of diisobutylaluminium hydride in toluene.
  • the lactone slowly dissolves and after a further 2 hours at room temperature the reaction is quenched by the addition of methanol (6 ml) followed by treatment with a saturated aqueous solution of sodium hydrogen tartrate (95 ml).
  • the mixture is stirred at 40oC for 2 hours and the organic phase is then separated.
  • the lactol (3) (1.0g) is treated with ethylene glycol (1.0g) in benzene (50 ml) and a catalytic amount (a crystal) of toluene sulphonic acid is added.
  • the mixture is heated under a Dean and Stark head for 20 hours and the solvent is then evaporated under vacuum to give the title compound (in which conversion of the
  • This compound (4) corresponds to the similar intermediate compound in the synthetic route to the bicyclo [2,2,2] octane compounds which is described in Example 4(2) but with the stereochemistry being different.
  • the compound (4) is converted by an exactly similar series of reactions to those described in Example 4 to give 5-exo-(6'-carboxyhex-2'Z-enyl)-6-endo-7-oxa-bicyclo [2,2,1] heptane which through reaction with phenylthiosemicarbazxde, in an analogous fashion to that used for a similar reaction in Examples 2 and 5 etc., is converted to 5-exo-(6'-carboxyhex-2'Z-enyl)-6-endo-[N-(phenylthiocarbamoyl)-hydrazonomethyl]-7-oxa-bicyclo [2,2,1] heptane.
  • the benzyl ether (1) (10.2g) is placed in a large flask (11.) with 30 ml THF (dry) under argon and 9-bora-bicyclo [3,3,1] nonane (9-BBN) in THF (90 ml of 0.5M solution) is added over 5-10 minutes at room temperature. The solution is refluxed for 30 hours maintaining the inert atmosphere, after which most of the compound has reacted at the double bond.
  • the hydroborated 'benzyl ether is cooled to 0oC while the argon atmosphere is replaced by carbon monoxide.
  • a solution of lithium trimethoxyaluminium hydride (62 ml of 0.7M) is prepared from lithium aluminium hydride and methanol in THF and added over 30-60 minutes with vigorous stirring maintaining a positive pressure of carbon monoxide in the system.
  • a vigorous uptake of gas is observed (ca. 1,000 ml) and after a further 1 hour of vigorous stirring the argon atmosphere is re-established and 82 ml of pH7 aqueous saturated phosphate buffer (buffer prepared from 97.5g
  • the benzyl ether/aldehyde (2) (10g) is dissolved in 100 ml of methanol containing 10 ml trimethyl orthoformate. A few crystals of p-toluene sulphonic acid are added and the mixture is kept overnight. The solution is treated with anhydrous sodium carbonate (0.5g) and water (20 ml) is slowly added with efficient mixing.
  • the benzyl ether/acetal (3) (10g) is dissolved in 100 ml of methanol and 300 mg of 10% palladium on charcoal * is added. The mixture is then hydrogentated at room temperature and atomospheric pressure. After take up of 1 molar equivalent of hydrogen the title compound is isolated in impure form as an oil in 100% yield by filtration of the mixture through Celite and evaporation of the methanol.
  • the acid/acetal (6) (0.5g) is dissolved in 20 ml of dioxane- water mixture (1:1) and the solution is heated at 40oC for 2.5 hours with an excess of 0.2M aqueous hydrochloric acid.
  • the title compound is isolated as an oil by extraction with ether followed by chromatography on silicic acid eluting with 5% ether in toluene
  • the acid/aldehyde (7) (100 mg) is heated with 4-phenylthio-semicarbazide (100 mg) in 5 ml dioxane at 60oC for 2 hours.
  • the solvent is removed in vacuo and the residue purified on Lipidex using the procedure described in Example 2(1) to give the title compound as an oil (126 mg) , v max (CH 3 OH) 274.5 nm, ⁇ max 16,650, ⁇ (CDCl 3 ) 1.
  • Example 8 2- ⁇ -(6'-Carboxyhex-2' Z-enyl) -3- ⁇ - 1 ' - [N-(phenyl- carbamoyl) -hydrazono] -ethyl ⁇ -6 , 6-dimethyl-bicyclo
  • [3,1,1] heptane is prepared as described in Example 7(7). This acid/aldehyde (1.1g) is dissolved in dry tetrahydrofuran (20 ml) and treated at 0oC under nitrogen with a 1M solution of methyl magnesium bromide in diethyl ether (12 ml). The mixture is stirred overnight and is then allowed to come to room temperature and is quenched by the addition of dilute aqueous hydrochloric acid.
  • the acid/alcohol mixture is treated with Jones reagent (1.25 ml) in acetone at 0oC for 30 minutes in an analogous fashion to that described in Example 2(2).
  • the reaction mixture is then quenched with water and the product immediately extracted with ether.
  • the ether solution is dried and evaporated and the oily residue is chromatographed on silica gel using increasing concentrations of ethyl acetate in toluene as eluant.
  • the bulk of the desired product is contained in the 20% v/v ethyl acetate/toluene fraction which is evaporated to give the title compound (0.625g), ⁇ (CDCl 3 ) 5.35 (m, 2H) , 2.18 (s, 3H) , 3.0-1.6 (m, 17H), 1.07 (s, 3H), 1.22 (s, 3H), 0.87 (d, 1H) , M + 306 and also 263 (M-43), 165 (M-141) and 125 (on methyl ester).
  • the methyl ester-butyl oxime derivative unlike the methyl ester, shows twin peaks en gas chromatography (syn/anti isomers).
  • the solvent is removed in vacuo and the residue is purified by gel partition chromatography on a column of Sephadex LH20 substituted with Nedox 1114 olefin oxide to 20% w/w (Lipidex) using as an eluant a mixture of (all proportions by volume) 100 parts of hexane, 100 parts of 1,2-dichloroethane, 5 parts of ethanol and 0.1% of the total of glacial acetic acid.
  • the chromatography gives the title compound as an oil (75 mg), 5(CDCl 3 ), 9.20 (br, 1H) , 8.30 (br, 1H) 5.40 (m, 2H) 1.98 (s, 3H) , 1.24 (s, 3H), 1.12 (s, 3H).
  • the vinyl ether (1) (2.0g) is heated in a sealed tube at
  • the vinyl ether (1) is passed in a stream of argon or nitrogen through a tube (1 cm x 10 cm) packed with glass wool and heated at 190oC, the product being condensed in a cold trap and distilled to give the title compound as an oil, b.p. 70-75oC/1 mm.
  • the acid (3) (2.0g) is treated with an ethereal solution of diazomethane (120 ml) and a few drops of methanol are added. The solution is stirred for 20 minutes and the solvent is then removed under vacuum to give the title compound as a yellow oil (2.2g, 100%).
  • the ester (4) (0.92g) is placed in a dry 100 ml round-bottomed flask under nitrogen and is treated at 0oC over 5 minutes using magnetic stirring with 9-bora-bicyclo [3,3,1] nonane (a-BBN) in tetrahydrofuran (20 ml of 0.5M solution).
  • a-BBN 9-bora-bicyclo [3,3,1] nonane
  • the reaction mixture is stirred at room temperature for 3 hours, and then 3N aqueous sodium hydroxide (3.3 ml, 10 mmol) is added, followed by 30% v/v aqueous hydrogen peroxide (3.3 ml) over a period of 10 minutes, cooling being required to control the resulting exothermic reaction.
  • the aldehyde ester (6) (0.075g) is treated with 0.2N 5% v/v aqueous methanolic potassium hydroxide at 40oC for 2 hours. The solution is then neutralized with 2N aqueous hydrochloric acid and extracted with ether (3 x 20 ml). The extracts are dried over magnesium sulphate and the solvent evaporated to give the title compound as an oil (0.065g, 65%), ⁇ (CDCl 3 ) 0.75 (s, 3H) , 1.22 (s, 3H), 5.45 (m, 2H) , 9.6 (br, 1H) , 9.71 (s or finely split d, 1H) .
  • This aldehyde acid (7) is obtained as a compound having a 2-formyl substituent with either the ⁇ or ⁇ configuration.
  • the formation of a single compound from the aldehyde ester (6) which is a mixture of compounds having a 2-formnyl substituent with either an exo or an endo configuration is due to the epimerisation resulting from the use of the base to effect de-esterification. It has not been possible, however, to identify which of the two configurations should be assigned to the 2-formyl substituent of the aldehyde acid.
  • the dioxane is removed in vacuo, and the resulting product is chromatographed on Sephadex LH20 substituted by Nedox 1114 olefin oxide to 20% w/w, eluting with (all proportions by volume) 100 parts of hexane, 100 parts of 1,2-dichloroethane and 5 parts of ethanol with 0.1% of the total of glacial acetic acid.
  • the chromatography gives the title compound as an oil
  • This compound (8) although obtained from the aldehyde acid (7) having either the a or ⁇ configuration at the 2-substituent, itself appears to be a mixture of the 2- ⁇ and 2- ⁇ compounds, rather than one of these compounds, owing to the basic conditions used in the formation of the compound.
  • This ester is hydrolysed by heating in aqueous methanolic (2:1, CH 3 OH/H 2 O) 0.1N potassium hydroxide for three hours at 40oC.
  • the mixture is diluted with water and extracted once with ether.
  • the aqueous layer is then acidified to pH 4 and extracted with ether. Evaporation of the solvent gives the title compound as an oil, ⁇ max (CH 3 OH) 263 nm, ⁇ max 480, ⁇ (CDCl 3 ) 5.01 (s, 2H), 5.39 (m, 2H) , 5.65 (m, 2H) , 6.75 (d, 1H), 6.90-7.50 (m, 4H) ; M + 387 (as methyl ester).
  • the p-fluorobenzyloxamine hydrochloride is prepared as follows. N-Hydroxyphthalimide (12.0g) in 130 ml dimethyl sulphoxide is treated with anhydrous finely divided potassium carbonate (6.6g), when the dark red colour of the anion develops. The mixture is then treated dropwise at room temperature with p-fluorobenzyl chloride (20g) and the mixture is stirred overnight or until the red colour is discharged. The reaction mixture is poured into water, and the resultant crystalline product is filtered off. Recrystallisation from ethanol gives N'-p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4g, 82%), m.p. 156-157oC.
  • the imide (13.5g) is boiled in 400 ml ethanol with 99% hydrazine hydrate (2.5g) for two hours. The mixture is cooled, 7 ml of cone, hydrochloric acid is added and the precipitate of phthal-hydrazide is removed by filtration. The solution is concentrated to dryness and the salt taken up in water, washed with ether and then basified. The free base is taken into ether to give an
  • Example 11 1 ⁇ -Hydroxy-2 ⁇ -(6'-carboxyethyl-2'Z-enyl)-38-(O-di phenylmethyloxyiminomethyl)-cyclopentane (1) 6-(1'3'-Dioxacyclopent-2-'yl)-2-oxabicyclo [3,3,0] octane-3-one 6-Formyl-2-oxabicyclo [3,3,0] octane-3-one (2.0g) is heated at 60 C in benzene (50 ml) with ethylene glycol (1 ml) and a trace of toluene-p-sulphonic acid under a Dean and Stark head.
  • reaction mixture is cooled and treated with water (20 ml) and 10% w/v aqueous NaHCO 3 (20 ml) .
  • the organic phase is separated, washed with water, dried and concentrated to give the title compound in 95% yield, v max (film) 1750 cm -1 .
  • the starting material is prepared by the treatment of 1,3-cyclohexadiene with dichloroacetyl chloride, followed by dechlorination with zinc and acetic acid of the resulting adduct to give bicyclo [4,2,0]-oct-2-en-7-one.
  • This compound is subjected to Baeyer-Villiger oxidation to give 7-oxabicyclo [4,3,0] non-2-en- 8-one which is treated with thallium (III) nitrate under carefully controlled conditions to give 6-formyl-2-oxabicyclo [3,3,0] octane-3-one having properties identical with those reported by Corey and Ravindranathan, Tetrahedron Letters, 1971, 4753.
  • Dimesyl sodium in DMSO (2.05 ml) is added dropwise to a solution of (4-carboxy-n-butyl)-tri ⁇ henylphosphonium bromide (2.3g) (dried before use) in 3 ml of DMSO.
  • a solution of the hydroxy/acetal (2) (0.5g) in 5 ml of DMSO is added dropwise a solution of the hydroxy/acetal (2) (0.5g) in 5 ml of DMSO and the mixture is stirred overnight.
  • the reaction mixture is then diluted with water (50 ml) and extracted with ethyl acetate.
  • the cooled aqueous layer is acidified with dilute HCl to pH 4 and extracted with ethyl acetate.
  • the hydroxy/acid/aldehyde (4) (50 mg) is heated at 60oC for 2 hours in pyridine (5 ml) with diphenylmethyloxvamine hydrochloride (70 mg, prepared by an analogous route to that described in Example 10 for o-p-fluorobenzyl-oxyamine hydrochloride).
  • the pyridine is removed in vacuo and the residue partitioned between water (pH 4) and ether.
  • the (2'-diphenylmethoxyethyl)-oxyamine hydrochloride is prepared from 1-chloro-2-(diphenylmethoxy) -ethane in an analogous fashion to that described in Example 10 for p-fluorobenzyloxyamine hydrochloride.
  • Example 13 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-[N- (dibenzylaminoacety1) -hydrazonomethyl]-bicyclo [2,2,1] heptane 5-endo-(6'-Carboxyhex-2' Z-enyl) -6-exo-formyl-bicyclo [2,2,1] heptane (100 mg) is heated at 60oC for two hours in ethanol with a 50% excess of (dibenzylaminoacetyl) -hydrazine. The solvent is evaporated off and the residue is chromatographed using the system described in Example 12 to give the title compound as an oil (129 mg), ⁇ max (CH 3 OH) 232 nm (shoulder), ⁇ max 10,270, and 215 nm
  • the (dibenzylaminoacetyl)-hydrazine used in this Example is prepared as follows. Ethyl bromoacetate (8.35g) in sodium dried benzene is added slowly to dibenzylamine (10.7g) and the mixture stirred for three hours. The mixture is then filtered and the solvent removed to give a residue which is a mixture of the hydrobromide of dibenzylamine and the ethyl ester of dibenzylaminoacetic acid. These compounds are separated by differential crystallisation from ethanol, the hydrobromide, m.p. 227oC, crystallising from hot ethanol and the ester, m.p. 54.9oC from ethanol at -20oC after standing overnight.
  • the ester (3g) is added slowly to hydrazine (3g) in dioxane and the mixture is refluxed.
  • the (dibenzylaminoacetyl) -hydrazine crystallises from the mixture and is recrystallised from cold ether, m.p. 124.2oC.
  • Example 14 5-endo-(6 '-Carboxyhex-2' Z-enyl) -6-exo-(N-benzoxazol- 2-yl-hydrazonomethyl) -bicyclo [2,2,1] heptane 5-endo-(6'-Carboxyhex-2' Z-enyl) -6-exo-formyl-bicyclo [2,2,1] heptane (100 mg) is heated at 60oC for two hours in pyridine/dioxane with benzoxazol-2-yl hydrazine hydrochloride (150 mg). The solvent is then evaporated in vacuo and the residue is partitioned between water (pH 4) and ether. The ether layer is dried (MgSO 4 ) and evaporated. The residue is chromatographed using the system described in Example 7 to give the title compound as an oil
  • Example is prepared from 2-chlorobenzoxazole b.p. 80-2oC/15 mm, which is in turn prepared from 2-mercaptobenzoxazale by the procedure described in the Journal of the Chemical Society, 1965, 4393.
  • 2-chlorobenzoxazale is heated in dioxane for two hours with an equimolar proportion of hydrazine and the benzoxazol-2-yl hydrazine hydrochloride is precipitated by the addition of ether to the reaction mixture.
  • Example 15 5-endo-(6'-Carboxyhex-2'Z-enyl)-6-exo-(N-p-toluene- sulphonylhydrazonomethyl) -bicyclo [2,2,1] heptane 5-endo-(6'-Carboxyhex-2' Z-enyl) -6-exo-formyl-bicyclo [2,2,1] heptane (100 mg) is heated at 60oC for two hours in tetrahydrofuran (5 ml) with p-toluene sulphonyi hydrazide.
  • the p-toluene sulphonyi hydrazide used in this Example is prepared by reacting p-toluene sulphonyi chloride with hydrazine hydrate.
  • the benzophenone hydrazone used in this Example is prepared by reacting refluxing benzophenone in ethanol with a 3-molar excess of hydrazine hydrate for three hours, then cooling the reaction mixture to -20°C to crystallise the hydrazone, m.p. 99.1°C.
  • Example 17 Further compounds
  • Each of the compounds contains an unmodified 6-carboxyhex-2 Z- enyl group.
  • the free acids in the case of these compounds and also those described in previous examples, are convertible to the methyl esters by solution in methanol, using warming and addition of NaHCO 3 as necessary, followed by the addition of an excess of ethereal diazomethane to the methanolic solution, standing, and the removal of solvent.
  • Physical data on the compounds are presented in Tables 2 and 3, U.V., M.S., and N.M.R. data being given for compounds 2, 3, 10 and 11 and analysed N.M.R. data for the remaining semicarbazone and thiosemicarbazone derivatives.
  • the U.V. data is for a methanolic solution and the N.M.R. data is given as ⁇ values relating to a CDCl 3 solution, referred to (CH 3 ) 4 Si.
  • Example 1 8 In vitro tests of biological activity
  • Human Platelet System Platelet-rich plasma obtained from fresh, citrated human blood. Addition of the 11,9-(epoxymethano) PGH (1 x 10 -7 to
  • a hyphen indicates that the particular test was not carried out on the compound in question.
  • Each of a group of six male Sprague-Dawley rats anaesthetised with pentabarbitone was injected intravenously with 40 ⁇ g/kg of collagen followed, 15 minutes later, by 80 ⁇ g/kg of collagen, which gives a dose-dependent and reproducible fall in platelet count.
  • the rats were treated intravenously with a dose of lmg/kg of 5-endo (6'-carboxyhex- 2'Z-enyl)-6-exo- ⁇ 1'-[N-(phenylthiocarbamoyl)-hydrazono]ethyl ⁇ -bicyclo [2,2,1] heptane prepared as described in Example 2.
  • the guinea pig was treated intravenously with a dose of 1 mg/kg of 5-endo (6'-carboxyhex-2 ' Z-enyl) -6-exoj 1' - [N-(phenylthiocarbamoy1) -hydrazono]-ethyl ⁇ -bicyclo [2,2,1] heptane prepared as described in Example 2.
  • the bicyclo [2,2,1] heptane thealternate treatments at 15 minute intervals with collagen and 11,9-(epoxymethano) PGH 2 were repeated, the second treatment with the latter compound being followed after 15 minutes by a final treatment with collagen.

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US5449827A (en) * 1993-04-10 1995-09-12 Huels Aktiengesellschaft Azomethine, a process for the preparation thereof and also its use

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US5716989A (en) * 1990-03-28 1998-02-10 Schering Aktiengesellschaft Bicyclo 3.3.0!octane derivatives, process for their production and their pharmaceutical use
US5449827A (en) * 1993-04-10 1995-09-12 Huels Aktiengesellschaft Azomethine, a process for the preparation thereof and also its use

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GB2137611B (en) 1985-04-11
ZA814307B (en) 1983-02-23
AU6389186A (en) 1987-01-15
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GB8330230D0 (en) 1983-12-21
AU582020B2 (en) 1989-03-09
JPH045660B2 (el) 1992-02-03
EP0111955A1 (en) 1984-06-27
AU562305B2 (en) 1987-06-04
NZ197558A (en) 1985-05-31
GB2081258A (en) 1982-02-17
US4596823A (en) 1986-06-24
JPH03227964A (ja) 1991-10-08
US5081282A (en) 1992-01-14
JPS62228040A (ja) 1987-10-06
US4945106A (en) 1990-07-31
DE3173492D1 (en) 1986-02-27
US5025034A (en) 1991-06-18
CA1246594A (en) 1988-12-13
GB2137611A (en) 1984-10-10
EP0043292A3 (en) 1982-12-15
EP0043292B1 (en) 1986-01-15
JPH02218642A (ja) 1990-08-31
EP0043292A2 (en) 1982-01-06
GB2081258B (en) 1984-11-07
EP0111955B1 (en) 1986-09-17
US5028733A (en) 1991-07-02

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